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International Transporter Consortium (ITC) Workshop 3 – Transporters in Drug Development Pre-conference
Monday, March 13, 2017 – Tuesday, March 14, 2017
Omni Shoreham Hotel, Washington, DC 

AGENDA
*Session descriptions included below
DAY 1 | MONDAY, MARCH 13, 2017
 8:15 - 8:30 am Welcome and Opening Remarks
Session 1: Membrane Transporters in Human Health and Pathobiology: From Biomarkers to Therapy
Moderators: Kim Brouwer (University of North Carolina, Chapel Hill) and Joseph Polli (GlaxoSmithKline)
 8:30 - 9:00 am Renal Transporters, Kidney Disease and Toxicity
Jonathan Himmelfarb, MD
University of Washington, Seattle, WA
9:00 - 9:30 am Hepatic Phospholipid and Bile Acid Transport Deficiencies: Therapeutic/Clinical Implications
Ronald Oude Elferink, PhD
Academic Medical Center, Amsterdam, Netherlands
9:30 - 10:00 am Gout and Uric Acid: From Disease to Transporters to Therapy
Jeffrey N. Miner, PhD
Ardea Biosciences, San Diego, CA
10:00 - 10:30 am Break
Session 2: Imaging and Pharmacokinetics of Intracellular Distribution
Moderators: Shiew-Mei Huang (U.S. Food and Drug Administration) and Ken Korzekwa (Temple University)
10:30 - 11:00 am Modeling Intracellular Concentrations with In Vitro Imaging and Liver Perfusion Studies
Ken Korzekwa, PhD
Temple University School of Pharmacy, Philadelphia
11:00 - 11:30 am Imaging Studies with the Transporter Probe 99mTc-Mebrofenin Reveal Altered Hepatic Exposure in Patients with Non-Alcoholic Steatophatitis (NASH)
Kim L. Brouwer, PharmD, PhD
University of North Carolina, Chapel Hill, NC
 11:30 - 12:00 pm Is Prediction of Tissue Exposure from In Vitro Data Using PBPK Modeling Possible? Confirmation by PET Imaging to Study the Clinical Disposition of Membrane Transporter Substrates
Yuichi Sugiyama, PhD
RIKEN, Kanagawa, Japan
12:00 - 1:00 pm Lunch and Poster Session
Session 3: Recent and Emerging Transporters
Moderators: Maciej Zamek-Gliszczynski (GlaxoSmithKline) and Richard Kim (University of Western Ontario) 
1:00 - 1:30 pm New Developments in Renal Drug Transport
Adrian S. Ray, PhD
Gilead Sciences, Foster City, CA
1:30 -  2:00 pm OATP2B1: In Vitro, Proteomic, and Clinical PK Relevance in GI and Liver
Jashvant D. Unadkat, PhD
University of Washington, Seattle, WA
2:00 - 2:30 pm Emerging Importance of Nutrient Transporter-Mediated DDIs
Yan Zhang, PhD
Incyte Corporation, Wilmington, DE
2:30 - 3:00 pm Break
Session 4: Modeling of Transporters from Molecular Mechanisms to PBPK
Moderators: Aleksandra Galetin (University of Manchester) and Pär Matsson (Uppsala University)
3:00 - 3:30 pm Inhibitor Discovery for the Human GLUT1 from Homology Modelling and Virtual Screening
Avner Schlessinger, PhD
Mount Sinai School of Medicine, New York, NY
3:30 - 4:00 pm Computational Modeling to Predict the Functions and Impact of Drug Transporters
Pär Matsson, MD
Uppsala University, Uppsala, Sweden
4:00 - 4:30 pm PBPK Modeling of Renal Impairment: What is Missing?
Aleksandra Galetin, PhD
University of Manchester, Manchester, United Kingdom
4:30 - 5:30 pm Breakout Sessions for Whitepapers
5:30 - 7:00 pm Poster Session and Receptions

DAY 2 | TUESDAY, MARCH 14, 2017
 7:15 - 8:15 am Breakout Sessions for Whitepapers
Session 5: Transporter Genomics: Genomewide and Massively Parallel Sequencing Studies
Moderators: Kathy Giacomini (University of California San Francisco) and Mikko Niemi (University of Helsinki)
8:30 - 9:00 am Massively Parallel Sequencing of Drug Transporters: SLCO1B1 and Beyond
Mikko Niemi, MD, PhD
University of Helsinki, Helsinki, Finland
 9:00 - 9:30 am Genomewide Studies Reveal Transporters as Determinants of Drug Response
Kathleen M. Giacomini, PhD
University of California San Francisco, San Francisco, CA
 9:30 - 10:00 am Na+/Citrate Transporter [SLC13A5] Variants in Epilepsy and Developmental Delay
Ana M. Pajor, PhD
University of California San Diego, La Jolla, CA
10:00 - 10:30 am Break
Session 6: Biomarkers and Probes for Clinical Studies
Moderators: Lei Zhang (U.S. Food and Drug Administration) and Xiaoyan Chu (Merck)
10:30 - 11:00 am Endogenous Biomarkers for Renal Transporters
Hiyouki Kusuhara, PhD
University of Tokyo, Tokyo, Japan
11:00 - 11:30 am Endogenous Biomarkers for OATP1B: Preclinical to Clinical Translations
Yurong Lai, MD, PhD
Gilead Sciences, Foster City, CA
11:30 - 12:00 pm Pharmacokinetic Evaluation of a Drug Transporter Cocktail Consisting of Digoxin, Furosemide, Metformin, and Rosuvastatin
Mitchell Taub, PhD
Boehringer Ingelheim, Ridgefield, CT
12:00 - 1:00 pm Lunch and Poster Session
Session 7: Regulatory Issues in Transporter Mediated Drug-Drug Interactions
Moderators: Donald Tweedie (Merck) and Yurong Lai (Bristol-Myers Squibb)
1:00 - 1:30 pm FDA Perspective
Lei Zhang, PhD
US Food and Drug Administration, Silver Spring, MD
1:30 - 2:00 pm A European Perspective
Eva Gil Berglund, PhD
Medical Products Agency, Uppsala, Sweden
2:00 - 2:15 pm Case Study 1: Industry/Academia
2:15 - 2:30 pm Case Study 2: Industry/Academia
2:30 - 2:45 pm Case Study 3: Industry/Academia
2:45 - 3:00 pm Presentation from IQ Drug Metabolism Transporter Subgroup
Speakers TBD
3:00 - 4:00 pm Panel Discussion with Academic, Industry and Regulatory Scientists
Kathleen M. Giacomini, PhD, University of California San Francisco, San Francisco, CA
Joseph W. Polli, PhD, GlaxoSmithKline, King of Prussia, PA
Kathleen Hillgren, PhD, Eli Lilly, Indianapolis, IN
Shiew-Mei Huang, PhD, US FDA, Silver Spring, MD
Eva Gill Berglund, PhD, Medical Products Agency, Uppsala, Sweden
4:00 - 4:15 pm Closing Remarks and End of Workshop
4:15 - 5:15 pm Open Forum to Provide Feedback to ITC

Session Descriptions
Session 1 | Membrane Transporters in Human Health and Pathobiology: From Biomarkers to Therapy
Membrane transporters have a diversity of functions, from creating an efflux barrier against a drug to absorbing essential nutrients across membranes.  Over the past decade, the interest in transporters within the ITC community has continued to grow from an initial focus on drug disposition and drug interactions to understanding the important role of membrane transporters in the disposition of nutrients and other endogenous compounds that impact human health and disease.  This session will highlight recent work in the membrane transporter field from biomarkers to therapy related to kidney injury, hepatic dysfunction and chronic disease.  The goal is to demonstrate the diverse cellular functions of membrane transporters as well as the critical importance of these processes to human health.   

Session 2 | Imaging and Pharmacokinetics of Intracellular Distribution 
Unbound intracellular concentrations are needed to predict the target and off-target activity of many drugs. Although the free drug hypothesis states that unbound intracellular and unbound extracellular drug concentrations will be equal at equilibrium, transporter activity can greatly alter intracellular concentrations. Direct measurement of unbound intracellular concentrations is difficult and modeling approaches have been used to convert measured in vitro and in vivo concentrations to estimates of intracellular concentrations in the presence of transporters. This session will discuss recent studies that use cellular and in vivo imaging, along with preclinical and clinical pharmacokinetic models to provide estimates of unbound intracellular drug concentrations.

Session 3 | Recent and Emerging Transporters
This session will highlight transporters of emerging clinical relevance to drug disposition and interactions.  Emphasis will be placed on new mechanistic insight into intestinal, hepatic, and renal transport.  Specifically, the recently-recognized importance of OAT2 in the kidney will be discussed.  Importance of OATP2B1 as an intestinal and hepatic uptake pathway will be presented from a victim and perpetrator DDI perspective.  Finally, nutrient transporter-mediated DDIs will be highlighted, with emphasis on intestinal THTR2 inhibition.  The ultimate goal of the session is to stimulate discussion on whether there is sufficient clinical evidence to revise and/or expand ITC recommendations on transporter evaluation in drug development.

Session 4 | Modeling of Transporters from Molecular Mechanisms to PBPK
This session will discuss the use of computational modelling across multiple aspects of transporter science, ranging from the identification of novel transporter ligands, the uncovering of mechanisms of substrate recognition, to the delineation of transporter effects in clinical trial data. The presentations will discuss use of multiple sources of data in transporter modelling, including X-ray crystallographic protein structure data, ligand structural data, and in vitro and clinical data on substrate transport and transporter inhibition. Current state-of-the-art will be outlined, and future directions in transporter modelling will be suggested—from structure- and ligand-based approaches to drug–transporter interaction modelling, to physiologically-based pharmacokinetic modelling of transporter-mediated disposition in special populations  

Session 5 | Transporter Genomics: Genomewide and Massively Parallel Sequencing Studies
Genomewide association studies have ushered in a new understanding of the role of common genetic polymorphisms in variation in drug disposition and response.  From these studies, common variants in membrane transporters in the liver and kidney have been discovered to be major determinants of variation in pharmacokinetics and pharmacodynamics of many prescription drugs.  In this session, we will present new information on the role of common genetic variants in transporters in the liver and kidney on drug disposition and response.   That information will be presented in the context of other factors that contribute to pharmacokinetic and pharmacodynamics such as drug dose and patient demographic characteristics.  New information on the effects of less common and rare variants in membrane transporters on drug disposition and response will be presented. Collectively, the session will provide the attendees with a rich overview of the effects of common and rare variants in hepatic and renal transporters on variation in drug disposition, toxicity and response.

Session 6 | Biomarkers and Probes for Clinical Studies
Transporter function could be modulated by multiple factors including genetic status, disease states or the presence of modulating drugs.  Transporter-mediated drug interactions need to be evaluated as part of risk assessment during drug development.  Decision criteria based on in vitro DDI assessments are recommended by the regulatory agencies to help determine the need for in vivo drug interaction evaluation.  Endogenous biomarkers and probe substrates for various transporters are helpful in understanding the in vivo effect of perpetrator drugs on transporters.  The selectivity profiles of endogenous biomarkers and probe substrates for various transporters need to be well characterized for study design and data interpretation.  This session will highlight recent progress on identifying novel transporter biomarker probes for renal and hepatic transporters.  Furthermore, the clinical evaluation of transporter cocktail probe substrates, which allows simultaneous assessment of a perpetrator drug’s interaction potential on multiple transporters, will be discussed.  

Session 7: Regulatory Issues in Transporter Mediated Drug-Drug Interactions
An updated DDI guidance is expected from the FDA. Drug-drug interaction (DDI) guidances from regulatory agencies (e.g., FDA, EMA and PMDA) have included recommendations on evaluating transporter-mediated DDIs in drug development.  Regulatory scientists have considerable experience in applying their DDI guidances and in responding to submissions from sponsors in relation to transporters and drug development.  This session offers an opportunity for direct interaction with regulatory scientists to hear their perspectives first hand.   Additionally, there will be case studies presented by industry and academic scientists offering insights into issues associated with transporters in drug development.  A panel discussion with key experts in the field of drug transporters from academia, industry and regulatory agencies will give the participants an opportunity to air their views, offer alternate perspectives and participate in an open discussion.




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